ABSTRACT The objective of this project is to identify sub-cellular and molecular mechanisms of skeletal muscle dysfunction that are responsible for chronic weakness in sepsis survivors. Using the knowledge obtained, this project will elucidate potential therapeutic interventions targeting post-sepsis chronic muscle weakness. Over 1 million sepsis survivors are now discharged from the hospital every year, and a majority of these survivors report reduced quality of life due to considerable muscle weakness lasting for years after hospital discharge. However, the lack of an appropriate animal model has been a critical barrier to identifying the changes which persist long after recovery from sepsis. We recently developed a new mouse model that has enabled us to evaluate long-term muscle quality and function in severe sepsis survivors. Our preliminary studies demonstrate that sepsis-surviving mice exhibit significant skeletal muscle weakness, even after bacterial infection and inflammation are resolved and muscle mass is recovered, giving us the unique opportunity to evaluate molecular mechanisms of muscle weakness beyond the muscle wasting phenotype. Skeletal muscles from these sepsis-surviving mice also show histological abnormalities, significant nitro-oxidative damage, and profound structural and functional defects in mitochondria. These preliminary results support our central hypothesis that sepsis-induced oxidative damage causes mitochondrial dysfunction and sarcomeric protein damage, both of which remain long after sepsis recovery, and these are the major contributors to the sustained skeletal muscle weakness in sepsis survivors. Specific Aims to test the hypothesis are: (1) To determine mitochondrial damage and dysfunction in sepsis-surviving mice; (2) To investigate sarcomeric protein damage and its causal mechanisms in sepsis-surviving mice; and (3) To formulate therapeutic strategies to ameliorate post-sepsis chronic muscle weakness.